Since Rosenberg et al reported that cisplatin (abbreviated as CDDP hereunder) has antitumor activity (Nature 222, 385 (1969)), many researchers have eagerly investigated to seek platinum complexes with a view of finding ones having antitumor activities. For example, some of these compounds appear in Japanese Patent Publication No. 5599/84, Japanese Patent Public Disclosure No. 77694/82, etc.
Although the known platinum complexes including CDDP were recognized to exhibit a broad spectrum of antitumor activities, their dosage amounts and the sorts of tumors which could be treated were limited because these complexes have very serious nephrotoxicity. In addition, it is observed that these platinum complexes generally bind to plasma proteins so as to be converted into an inactivated form.
The inventors of this invention have studied various platinum complexes in order to identify those having high antitumor activities and less toxicity. Finally, we found the compounds of this invention and confirmed that these complexes are suitable for use as an antitumor agent.
The compounds of this invention are prepared by the following method.
Platinum(II)potassium chloride is reacted with a diamine derivative represented by the formula (II): ##STR5## wherein A, R.sub.1, R.sub.2, R.sub.3, R.sub.4, l and m are the same as defined above to give the corresponding dichloro compound [formula (I) (n is 0, X and Y are chlorine)]. The resulting dichloro compound is oxidized with hydrogen peroxide to give a novel platinum complex of the formula (I) [n=1, X=Y=Cl] defined above. The dichloro compound is converted to dinitrate form with use of silver nitrate, and then reacted with a dicarboxylic acid to give a novel platinum complex of the formula (I) [n is 0, X and Y are ##STR6## defined above.
Diamine derivatives which can be used in this invention include 2-aminomethylpyrrolidine, (S)-2-aminomethylpyrrolidine, (R)-2-aminomethylpyrrolidine, 2-(1-aminoethyl)pyrrolidine, 2-aminomethyl-1-methylpyrrolidine, 2-aminomethyl-1-ethylpyrrolidine, 2-aminomethyl-1,5-dimethylpyrrolidine, 1-(2-aminoethyl)pyrrolidine, 2-aminoethylazetidne, 2-aminomethylaziridine, and the like.
Dicarboxylic acids which are useful in this invention include oxalic acid, 1,1-cyclobutanedicarboxylic acid and their salts.
The platinum complex of this invention can be formulated by any desirable conventional method with a pharmaceutically acceptable carrier and, if necessary, an adjuvant.
For oral administration, the compound of this invention can be formulated into a solid preparation such as tablets, pills, granules, powder, capsules, or the like, or a liquid preparation such as solution, suspension, emulsion or the like. When the preparation is used for parenteral administration, the preparation is formulated into a suppository, injection, an intravenous drip infusion or the like. When the compound of this invention is formulated into tablets, pills, granules, powder or capsules, pharmaceutical carriers such as starch, sucrose, crystalline cellulose, kaolin, calcium carbonate, talc, magnesium carbonate and the like are preferably used. For preparation of an injection, it is preferred that the compound is dissolved in distilled water or an aqueous solution of a salt such as sodium chloride. For preparation of an intravenous drip infusion, the compound is dissolved in a suitable fluid therapy such as a physiological saline, a glucose-sodium chloride solution or the like. For the suppository, cacao butter, laurin, glycerogelatin, macrogol are preferably used as a base.
The amount of the compound in a formulated preparation is selected so as to be appropriately administered depending on the age and condition of individual patient being treated.
The compound of this invention is preferably administrated orally in a daily dose of from 200 to 400 mg/m.sup.2, and parenterally in a daily dose of from 100 to 200 mg/m.sup.2.
The compound of this invention has very low toxicity. For example, when ddY strain male mouse (5 week old, weighing 26-30 g) was intraperitoneally administered, the compound of this invention as an aqueous solution, the LD.sub.50 was higher than 80 mg/kg.
As described above, since the compound of this invention has high antitumor activity and low toxicity, and is easily soluble in water, it is very useful as a drug.